Combination of selected opioids with muscarine antagonists for treating urinary incontinence

ABSTRACT

Active compound combinations of compounds of group A, particularly opioids such as (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol or a salt thereof with a physiologically tolerated acid, and compounds of group B, particularly anti-muscarine agents such as oxybutynin or a salt thereof with a physiologically tolerated acid suitable for treatment of an increased urge to urinate or urinary incontinence. Related pharmaceutical formulations and methods of treatment of an increased urge to urinate or urinary incontinence are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation co-pending application Ser. No.10/803,187, filed Mar. 18, 2004, which in turn was a continuation ofInternational Patent Application No. PCT/EP02/10460, filed Sep. 18,2002, designating the United States of America, and published in Germanas WO 03/024444, the entire disclosure of which is incorporated hereinby reference. Priority is claimed based on Federal Republic of GermanyPatent Application No. DE 101 46 275.1, filed Sep. 18, 2001.

FIELD OF THE INVENTION

The invention relates to the use of a combination of compounds of groupA, in particular opioids, and compounds of group B, in particularanti-muscarine agents and other substances which have a predominantlyperipheral action, for the preparation of a medicament for treatment ofan increased urge to urinate or urinary incontinence and tocorresponding medicaments and methods for treatment of an increased urgeto urinate or urinary incontinence.

BACKGROUND OF THE INVENTION

Urinary incontinence is the involuntary discharge of urine. This occursin an uncontrolled manner when the pressure within the urinary bladderexceeds the pressure needed to close the ureter. Causes can be, on theone hand, an increased internal pressure in the bladder (e.g., due todetrusor instability) with the consequence of urgency incontinence, and,on the other, a reduced sphincter pressure (e.g., following giving birthor surgical interventions) with the consequence of stress incontinence.The detrusor is the coarsely bundled multilayered bladder wallmusculature, contraction of which leads to voiding of urine, and thesphincter is the closing muscle of the urethra. Mixed forms of thesetypes of incontinence and so-called overflow incontinence or reflexincontinence (e.g., following damage to the spinal cord) occur. Thus,for example, urinary incontinence, an urge to urinate and an increasedfrequency of micturition are all possible symptoms of benign prostatehyperplasia. Further details of this complex are to be found in Chutka,D. S, and Takahashi, P. Y., 1998, Drugs 560: 587-595.

The urge to urinate is the state, aimed at voiding of urine(micturition), of increased bladder muscle tension as the bladdercapacity is approached (or exceeded). This tension acts here as astimulus to micturition. An increased urge to urinate is understood herein particular as the occurrence of premature or an increased andsometimes even painful urge to urinate up to so-called strangury. Thisconsequently leads to a significantly more frequent micturition. Causescan be, inter alia, inflammations of the urinary bladder and neurogenicbladder disorders, and also bladder tuberculosis. However, not all thecauses have yet been clarified.

An increased urge to urinate and also urinary incontinence are perceivedas extremely unpleasant and there is a clear need among persons affectedby these indications to achieve an improvement which is as long-term aspossible.

An increased urge to urinate and in particular urinary incontinence areconventionally treated with medicaments using substances which areinvolved in the reflexes of the lower urinary tract (Wein, A. J., 1998,Urology 51 (Suppl. 21): 43-47). These are usually medicaments which havean inhibiting action on the detrusor muscle, which is responsible forthe internal pressure in the bladder. These medicaments are, e.g.,parasympatholytics, such as oxybutynin, propiverine or tolterodine,tricyclic antidepressants, such as imipramine, or muscle relaxants, suchas flavoxate. Other medicaments, which in particular increase theresistance of the urethra or of the neck of the bladder, show affinitiesfor α-adrenoreceptors, such as ephedrine, for β-adrenoreceptors, such asclenbutarol, or are hormones, such as oestradiol.

The review article by K. E. Andersson et al. “The pharmacologicaltreatment of urinary incontinence”, BJU International (1999), 84,923-947 gives an accurate insight here into the therapeutics andtreatment methods used, in particular in respect of anti-muscarineagents and other substances having a peripheral action.

Certain diarylmethylpiperazines and -piperidines are also described forthis indication in WO 93/15062. For tramadol also a positive effect onbladder function has been demonstrated in a rat model of rhythmicbladder contractions (Nippon-Shinyaku, WO 98/46216). There arefurthermore investigations for characterization of the opioid sideeffect of urinary retention in the literature, from which someindications of the influencing of bladder functions by weak opioids,such as diphenoxylate (Fowler et al., 1987 J. Urol 138:735-738) andmeperidine (Doyle and Briscoe, 1976 Br J Urol 48:329-335), by mixedopioid agonists/antagonists, such as buprenorphine (Malinovsky et al.,1998 Anesth Analg 87:456-461; Drenger and Magora, 1989 Anesth Analg69:348-353), pentazocine (Shimizu et al. (2000) Br. J. Pharmacol. 131(3): 610-616) and nalbuphine (Malinovsky et al., 1998, loc. cit.), andby potent opioids, such as morphine ((Malinovsky et al., 1998 loc. cit.;Kontani and Kawabata, (1988); Jpn J. Pharmacol. September; 48(1):31) andfentanyl (Malinovsky et al., 1998 loc. cit.) result. Nevertheless, theseinvestigations were usually carried out in analgesically activeconcentrations.

In the case of the indications in question here, it should be rememberedthat it is in general a matter of very long-term uses of medicamentsand, in contrast to many situations where analgesics are employed, thoseaffected are faced with a situation which is very unpleasant but notintolerable. It is therefore to be ensured here—even more so than withanalgesics—that side effects are avoided if the person affected does notwant to exchange one evil for another. Also, analgesic actions are alsolargely undesirable during permanent treatment of urinary incontinence.

SUMMARY OF THE INVENTION

The object of the present invention was therefore to provide substancesor substance combinations which are helpful for treatment of anincreased urge to urinate or urinary incontinence and, at the activedoses, preferably at the same time show fewer side effects and/oranalgesic actions than known from the prior art, in particular show asynergistic effect for treatment of urinary incontinence.

It has now been found, surprisingly, that a combination of compounds ofgroup A, the opioids and other substances which have a central actionand can interact with opioid receptors and the effects of which can beantagonized by naloxone, or in particular substances which act via anopiate receptor, in particular the μ-receptor, and compounds of group B,which comprises muscarine antagonists and other substances which areknown to be active in urinary incontinence and have a predominantlyperipheral action, have an outstanding action on bladder function. Thesecombinations furthermore proved to be so active at very lowdoses—significantly beyond that expected—that it was possible to employthe combined active compounds in a low dose. As a result, in therapeuticuse the side effects which otherwise occur at the higher dosagesnecessary decrease significantly, while the therapeutic action isretained in full by this combination of peripheral anti-muscarine effectacting predominantly directly on the bladder or bladder musculature andcentral opioid effect or μ-receptor effect.

The invention accordingly provides the use of an active compoundcombination of at least one of the compounds A and at least one of thecompounds B, with compound A chosen from:

-   -   Group a) comprising: tramadol, O-demethyltramadol, or        O-demethyl-N-mono-demethyl-tramadol, optionally in the form of        their racemates, their isolated or pure stereoisomers, in        particular enantiomers or diastereomers, or in the form of        mixtures of the stereoisomers, in particular the enantiomers or        diastereomers, in any desired mixing ratio; in the form of their        acids or their bases or in the form of their salts, in        particular the physiologically acceptable salts, or in the form        of their solvates, in particular the hydrates;    -   Group b) comprising:        -   codeine        -   dextropropxyphene        -   dihydrocodeine        -   diphenoxylate        -   ethylmorphine        -   meptazinol        -   nalbuphine        -   pethidine (meperidine)        -   tilidine        -   tramadol        -   viminol        -   butorphanol        -   dextromoramide        -   dezocine        -   diacetylmorphine (heroin)        -   hydrocodone        -   hydromorphone        -   ketobemidone        -   levomethadone        -   levomethadyl acetate (1-α-acetylmethadol (LAAM))        -   levorphanol        -   morphine        -   nalorphine        -   oxycodone        -   pentazocine        -   piritramide        -   alfentanil        -   buprenorphine        -   etorphine        -   fentanyl        -   remifentanil        -   sufentanil

optionally in the form of their racemates, their isolated stereoisomers,in particular enantiomers or diastereomers, or in the form of mixturesof the stereoisomers, in particular the enantiomers or diastereomers, inany desired mixing ratio; in the form of their acids or their bases orin the form of their salts, in particular the physiologically acceptablesalts, or in the form of their solvates, in particular the hydrates;

-   -   Group c) comprising:    -   1-phenyl-3-dimethylamino-propane compounds according to the        general formula I

-   -   wherein    -   X is chosen from OH, F, Cl, H or OC(O)R⁷, where R⁷ is chosen        from C₁₋₃-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted,    -   R¹ is chosen from C₁₋₄-alkyl, branched or unbranched, saturated        or unsaturated, unsubstituted or mono- or polysubstituted,    -   R² and R³ in each case independently of one another are chosen        from H or C₁₋₄-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted,    -   or    -   R² and R³ together form a saturated C₄₋₇-cycloalkyl radical,        unsubstituted or mono- or polysubstituted,    -   R⁹ to R¹³ in each case independently of one another are chosen        from H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴,        NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃ CN, COOR¹⁴, NO₂,        CONR¹⁷R¹⁸; C₁₋₆-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted; phenyl,        unsubstituted or mono- or polysubstituted;        -   where R¹⁴ is chosen from C₁₋₆-alkyl; pyridyl, thienyl,            thiazolyl, phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted;            PO(O—C₁₋₄-alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl),            CO(C₁₋₅-alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₁₋₆H₄—R¹⁵, where R¹⁵ is            ortho-OCOC₁₋₃-alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁸ is            C₁₋₄-alkyl or 4-morpholino, wherein in the radicals R¹⁴, R¹⁵            and R¹⁶ the alkyl groups can be branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted;        -   where R¹⁷ and R18 in each case independently of one another            are chosen from H; C₁₋₆-alkyl, branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted; phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted,    -   or    -   R⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O,        OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH₂)₄ or OCH═CHO ring,

optionally in the form of their racemates, their isolated stereoisomers,in particular enantiomers or diastereomers, or in the form of mixturesof the stereoisomers, in particular the enantiomers or diastereomers, inany desired mixing ratio; in the form shown or in the form of theiracids or their bases or in the form of their salts, in particular thephysiologically acceptable salts, or in the form of their solvates, inparticular the hydrates;

-   -   Group d) comprising:    -   substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds        according to the general formula II

-   -   wherein    -   X is chosen from OH, F, Cl, H or OC(O)R⁷, where R⁷ is chosen        from C₁₋₃-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted,    -   R¹ is chosen from C₁₋₄-alkyl, benzyl, CF₃, OH, OCH₂—C₆H₅,        O—C₁₋₄-alkyl, Cl or F and

R⁹ to R¹³ in each case independently of one another are chosen from H,F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃,SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; C₁₋₆-alkyl, branchedor unbranched, saturated or unsaturated, unsubstituted or mono- orpolysubstituted; phenyl, unsubstituted or mono- or polysubstituted;

-   -   where R¹⁴ is chosen from C₁₋₆-alkyl; pyridyl, thienyl,        thiazolyl, phenyl, benzyl or phenethyl, in each case        unsubstituted or mono- or polysubstituted; PO(O—C₁₋₄-alkyl)₂,        CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl), CO(C₁₋₅-alkyl),        CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ is ortho-OCOC₁₋₃-alkyl or        meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is C₁₋₄-alkyl or        4-morpholino, wherein in the radicals R¹⁴, R¹⁵ and R¹⁶ the alkyl        groups can be branched or unbranched, saturated or unsaturated,        unsubstituted or mono- or polysubstituted;    -   where R¹⁷ and R18 in each case independently of one another are        chosen from H; C₁₋₆-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted; phenyl,        benzyl or phenethyl, in each case unsubstituted or mono- or        polysubstituted,    -   or    -   R⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O,        OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH₂)₄ or OCH═CHO ring,    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form shown or in the form of their acids or their bases or        in the form of their salts, in particular the physiologically        acceptable salts, or in the form of their solvates, in        particular the hydrates;    -   and/or    -   Group e) comprising:    -   6-dimethylaminomethyl-1-phenyl-cyclohexane compounds according        to the general formula III

-   -   wherein    -   X is chosen from OH, F, Cl, H or OC(O)R⁷, where R⁷ is chosen        from C₁₋₃-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted, and    -   R⁹ to R¹³ in each case independently of one another are chosen        from H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴,        NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂,        CONR¹⁷R¹⁸; C₁₋₆-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted; phenyl,        unsubstituted or mono- or polysubstituted;        -   where R¹⁴ is chosen from C₁₋₆-alkyl; pyridyl, thienyl,            thiazolyl, phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted;            PO(O—C₁₋₄-alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl),            CO(C₁₋₅-alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ is            ortho-OCOC₁₋₃-alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is            C₁₋₄-alkyl or 4-morpholino, wherein in the radicals R¹⁴, R¹⁵            and R¹⁶ the alkyl groups can be branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted;        -   where R¹⁷ and R18 in each case independently of one another            are chosen from H; C₁₋₆-alkyl, branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted; phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted,    -   or    -   R⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O,        OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH₂)₄ or OCH═CHO ring,    -   with the proviso that if R⁹, R¹¹ and R¹³ correspond to H and one        of R¹⁰ or R¹² corresponds to H and the other corresponds to        OCH₃, X may not be OH,    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form shown or in the form of their acids or their bases or        in the form of their salts, in particular the physiologically        acceptable salts, or in the form of their solvates, in        particular the hydrates;    -   and with at least one of the compounds B chosen from:        -   the anti-muscarine agents: atropine, oxybutinin,            propiverine, propantheline, emepronium, trospium,            tolterodine, darifenacin and α,α-diphenylacetic acid            4-(N-methylpiperidyl) ester, as well as duloxetine,            imipramine and desmopressin,    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form of their acids or their bases or in the form of their        salts, in particular the physiologically acceptable salts, or in        the form of their solvates, in particular the hydrates;    -   for the preparation of medicament for treatment of an increased        urge to urinate or urinary incontinence.

Surprisingly, it has been found that the combination of the substancesmentioned has a significantly positive influence on certainphysiological parameters, which are of importance in cases of anincreased urge to urinate or urinary incontinence. Each individual ofthese compounds can mean a significant alleviation in the symptomaticpicture of the patient affected.

In the context of this invention, alkyl or cycloalkyl radicals areunderstood as meaning saturated and unsaturated (but not aromatic),branched, unbranched and cyclic hydrocarbons, which can be unsubstitutedor mono- or polysubstituted. In this context, C₁₋₂-alkyl represents C1-or C2-alkyl, C₁₋₃-alkyl represents C1-, C2- or C3-alkyl, C₁₋₄-alkylrepresents C1-, C2-, C3- or C4-alkyl, C₁₋₅-alkyl represents C1-, C2-,C3-, C4- or C5-alkyl, C₁₋₆-alkyl represents C1-, C2-, C3-, C4-, C5- orC6-alkyl, C₁₋₇-alkyl represents C1-, C2-, C3-, C4-, C5-, C6- orC7-alkyl, C₁₋₈-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- orC8-alkyl, C₁₋₁₀-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-,C9- or C10-alkyl and C₁₋₁₈-alkyl represents, C1-, C2-, C3-, C4-, C5-,C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- orC18-alkyl. Furthermore, C₃₋₄-cycloalkyl represents C3- or C4-cycloalkyl,C5-cycloalkyl represents C3-, C4- or C5-cycloalkyl, C₃₋₆-cycloalkylrepresents C3-, C4-, C5- or C6-cycloalkyl, C₃₋₇-cycloalkyl representsC3-, C4-, C5-, C6- or C7-cycloalkyl, C₃₋₈-cycloalkyl represents C3-,C4-, C5-, C6-, C7- or C8-cycloalkyl, C₄₋₅-cycloalkyl represents C4- orC5-cycloalkyl, C₄₋₆-cycloalkyl represents C4-, C5- or C6-cycloalkyl,C₄₋₇-cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl,C₅₋₆-cycloalkyl represents C5- or C6-cycloalkyl and C₅₋₇-cycloalkylrepresents C5-, C6- or C7-cycloalkyl. In respect of cycloalkyl, the termalso includes saturated cycloalkyls in which one or 2 carbon atoms arereplaced by a heteroatom, S, N or O. However, the term cycloalkyl alsoincludes, in particular, mono- or poly-, preferably monounsaturatedcycloalkyls without a heteroatom in the ring as long as the cycloalkylis not an aromatic system. The alkyl and cycloalkyl radicals arepreferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl),1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl,2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl,cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and alsoadamantyl, CHF₂, CF₃ or CH₂OH, as well as pyrazolinone, oxopyrazolinone,[1,4]dioxane or dioxolane.

In connection with alkyl and cycloalkyl—as long as this is not expresslydefined otherwise—the term substituted here in the context of thisinvention is understood as substitution of at least one (optionally alsoseveral) hydrogen radical(s) by F, Cl, Br, I, NH₂, SH or OH, where“polysubstituted” or “substituted” in the case of polysubstitution is tobe understood as meaning that the substitution takes place both ondifferent and on the same atoms several times with the same or differentsubstituents, for example three times on the same C atom as in the caseof CF₃, or at different places as in the case of —CH(OH)—CH═CH—CHCl₂.Particularly preferred substituents here are F, Cl and OH. In respect ofcycloalkyl, the hydrogen radical can also be replaced by OC₁₋₃-alkyl orC₁₋₃-alkyl (in each case mono- or polysubstituted or unsubstituted), inparticular methyl, ethyl, n-propyl, i-propyl, CF₃, methoxy or ethoxy.

The term (CH₂)₃₋₆ is to be understood as meaning —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,(CH₂)₁₋₄ is to be understood as meaning —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—and —CH₂—CH₂—CH₂—CH₂—, (CH₂)₄₋₅ is to be understood as meaning—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂— etc.

An aryl radical is understood as meaning ring systems with at least onearomatic ring, but without heteroatoms in even only one of the rings.Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl orindanyl, in particular 9H-fluorenyl or anthracenyl radicals, which canbe unsubstituted or mono- or polysubstituted.

A heteroaryl radical is understood as meaning heterocyclic ring systemswith at least one unsaturated ring, which contain one or moreheteroatoms from the group consisting of nitrogen, oxygen and/or sulfurand can also be mono- or polysubstituted. Examples which may bementioned from the group of heteroaryls are furan, benzofuran,thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine,quinoline, isoquinoline, phthalazine, benzo-1,2,5thiadiazole,benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane,carbazole, indole and quinazoline.

In this context, in connection with aryl and heteroaryl, substituted isunderstood as meaning substitution of the aryl or heteroaryl by R²³,OR²³ a halogen, preferably F and/or Cl, a CF₃, a CN, an NO₂, an NR²⁴R²⁵,a C₁₋₆-alkyl (saturated), a C₁₋₆-alkoxy, a C₃₋₈-cycloalkoxy, aC₃₋₈-cycloalkyl or a C₂₋₆-alkylene.

In this context, the radical R²³ represents H, a C₁₋₁₀-alkyl, preferablya C₁₋₆-alkyl, an aryl or heteroaryl or an aryl or heteroaryl radicalbonded via a C₁₋₃-alkylene group, where these aryl and heteroarylradicals may not themselves be substituted by aryl or heteroarylradicals. The radicals R²⁴ and R²⁵ are identical or different and denoteH, a C₁₋₁₀-alkyl, preferably a C₁₋₆-alkyl, an aryl, a heteroaryl or anaryl or heteroaryl radical bonded via a C₁₋₃-alkylene group, where thesearyl and heteroaryl radicals may not themselves be substituted by arylor heteroaryl radicals. Alternatively, the radicals R²⁴ and R²⁵ togetherdenote CH₂CH₂OCH₂CH₂, CH₂CH₂NR²⁶CH₂CH₂ or (CH₂)₃₋₆, and the radical R²⁶denotes H, a C₁₋₁₀-alkyl, preferably a C₁₋₆-alkyl, an aryl or heteroarylradical or an aryl or heteroaryl radical bonded via a C₁₋₃-alkylenegroup, where these aryl and heteroaryl radicals may not themselves besubstituted by aryl or heteroaryl radicals.

The term salt in the context of this invention is to be understood asmeaning any form of the active compound according to the invention inwhich this assumes an ionic form or is charged and is coupled with acounter-ion (a cation or anion) or is in solution. This is also to beunderstood as meaning complexes of the active compound with othermolecules and ions, in particular complexes which are complex via ionicinteractions.

The term physiologically acceptable salt (in particular with cations orbases) in the context of this invention is understood as meaning saltsof at least one of the compounds according to the invention—usually a(deprotonated) acid—as the anion with at least one preferably inorganiccation, which are physiologically acceptable—in particular when used onhumans and/or mammals. Particularly preferred salts are those of thealkali metals and alkaline earth metals, but also with NH₄ ⁺, but inparticular (mono-) or (di-)sodium, (mono-) or (di-)potassium, magnesiumor calcium salts.

The term physiologically acceptable salt (in particular with anions oracids) in the context of this invention is furthermore understood asmeaning salts of at least one of the compounds according to theinvention—usually protonated, for example on the nitrogen—as the cationwith at least one anion, which are physiologically acceptable—inparticular when used on humans and/or mammals. In particular, in thecontext of this invention this is understood as meaning the salt formedwith a physiologically acceptable acid, namely salts of the particularactive compound with inorganic or organic acids which arephysiologically acceptable—in particular when used on humans and/ormammals. Examples of physiologically acceptable salts of particularacids are salts of hydrochloric acid, hydrobromic acid, sulfuric acid,methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro1b6-benzo[d]isothiazol-3-one (saccharic acid),monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid,a-liponic acid, acetylglycine, acetylsalicylic acid, hippuric acidand/or aspartic acid. The hydrochloride salt is particularly preferred.

Suitable salts in the context of this invention and in each usedescribed and each of the medicaments described are salts of theparticular active compound with inorganic or organic acids and/or asugar substitute, such as saccharin, cyclamate or acesulfam. However,the hydrochloride is particularly preferred.

Compounds of group c) and their preparation are known from DE 44 26 245A1 and U.S. Pat. No. 6,248,737. Compounds of group d) and e) and theirpreparation are known from DE 195 25 137 A1 and U.S. Pat. No. 5,733,936and US RE37355E.

In a preferred embodiment, for the use according to the invention thecompound A in group a) is chosen from:

-   -   tramadol, (+)-tramadol, (+)—O-demethyltramadol or        (+)—O-demethyl-N-mono-demethyl-tramadol,    -   preferably tramadol or (+)-tramadol,    -   in particular (+)-tramadol.

In a preferred embodiment, for the use according to the invention thecompound A in group b) is chosen from:

-   -   codeine    -   dextropropxyphene    -   dihydrocodeine    -   diphenoxylate    -   ethylmorphine    -   meptazinol    -   nalbuphine    -   pethidine (meperidine)    -   tilidine    -   viminol    -   butorphanol    -   dezocine    -   nalorphine    -   pentazocine    -   buprenorphine        preferably    -   codeine    -   dextropropxyphene    -   dihydrocodeine    -   meptazinol    -   nalbuphine    -   tilidine    -   buprenorphine

In a preferred embodiment, for the use according to the invention thecompound A in group c) is chosen from compounds according to formula Ifor which:

-   -   X is chosen from        -   OH, F, Cl, OC(O)CH₃ or H, preferably OH, F, OC(O)CH₃ or H,    -   and/or    -   R¹ is chosen from        -   C₁₋₄-alkyl, saturated and unsubstituted, branched or            unbranched; preferably CH₃, C₂H₅, C₄H₉ or t-butyl, in            particular CH₃ or C₂H₅, and/or    -   R² and R³ independently of one another are chosen from        -   H, C₁₋₄-alkyl, saturated and unsubstituted, branched or            unbranched; preferably H, CH₃, C₂H₅, i-propyl or t-butyl, in            particular H or CH₃, preferably R³═H,        -   or        -   R² and R³ together form a C₅₋₆-cycloalkyl radical, saturated            or unsaturated, unsubstituted or mono- or polysubstituted,            preferably saturated and unsubstituted, in particular            cyclohexyl.    -   and/or    -   R⁹ to R¹³, where 3 or 4 of the radicals R⁹ to R¹³ must        correspond to H, independently of one another are chosen from        -   H, Cl, F, OH, CF₂H, CF₃ or C₁₋₄-alkyl, saturated and            unsubstituted, branched or unbranched; OR¹⁴ or SR¹⁴, where            R¹⁴ is chosen from C₁₋₃-alkyl, saturated and unsubstituted,            branched or unbranched;            -   preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃        -   or R¹² and R¹¹ form a 3,4-OCH═CH ring    -   in particular        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H,                OCH₃ or SCH₃        -   or        -   if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH,            OCH₃, Cl or F, preferably Cl, one of R¹⁰ or R¹² also            corresponds to H while the other corresponds to OH, OCH₃, Cl            or F, preferably Cl,        -   or        -   if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is chosen from            CF₃, CF₂H, Cl or F, preferably F,        -   or        -   if R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also            corresponds to H while the other is chosen from OH, OC₂H₅ or            OC₃H₇.

In this context, it is particularly preferable for compounds of group c)if compounds of the formula I where R³═H are in the form of thediastereomers with the relative configuration 1a

-   -   in particular are used in mixtures with a higher content of this        diastereomer compared with the other diastereomer or as the        isolated diastereomer    -   and/or    -   the compounds of the formula I are used in the form of the        (+)-enantiomer, in particular in mixtures with a higher content        of the (+)-enantiomer compared with the (−)-enantiomer of a        racemic compound or as the isolated (+)-enantiomer.

In this context, it is particularly preferable if compound A chosen fromthe following group is used:

-   -   (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol    -   (2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,    -   (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,    -   (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol,    -   (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethylamino-2-methyl-pentan-3-ol,    -   (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanyl-phenyl)-pentan-3-ol,    -   (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethyl-pentan-3-ol,    -   (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenol,    -   (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,    -   (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,    -   (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,    -   (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (+)-(1R,2R)-acetic acid        3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl-propyl        ester,    -   (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxy-phenyl)-propan-1-ol,    -   (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol,    -   (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenol,    -   (2RS,3RS)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol        and    -   (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol,    -   preferably as the hydrochloride.

In a preferred embodiment, for the use according to the invention thecompound A in group d) is chosen from compounds according to formula IIfor which:

-   -   X is chosen from        -   OH, F, Cl, OC(O)CH₃ or H, preferably OH, F or H, in            particular OH,    -   and/or    -   R¹ is chosen from        -   C₁₋₄-alkyl, CF₃, OH, O—C₁₋₄-alkyl, Cl or F, preferably OH,            CF₃ or CH₃,    -   and/or    -   R⁹ to R¹³, where 3 or 4 of the radicals R⁹ to R¹³ must        correspond to H, independently of one another are chosen from        -   H, Cl, F, OH, CF₂H, CF₃ or C₁₋₄-alkyl, saturated and            unsubstituted, branched or unbranched; OR¹⁴ or SR¹⁴, where            R¹⁴ is chosen from C₁₋₃-alkyl, saturated and unsubstituted,            branched or unbranched;            -   preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH_(3 or R)                ¹² and R¹¹ form a 3,4-OCH═CH ring    -   in particular        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H,                OR¹⁴ or SCH₃, in particular OH or OC₁₋₃-alkyl,                preferably OH or OCH₃,        -   or        -   if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH,            OCH₃, Cl or F, preferably Cl, one of R¹⁰ or R¹² also            corresponds to H while the other corresponds to OH, OCH₃, Cl            or F, preferably Cl,        -   or        -   if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is chosen from            CF₃, CF₂H, Cl or F, preferably F,        -   or        -   if R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also            corresponds to H while the other is chosen from OH, OC₂H₅ or            OC₃H₇.        -   very particularly preferably        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:        -   Cl, F, OH, SH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH or            OR¹⁴, in particular OH or OC₁₋₃-alkyl, preferably OH or            OCH₃.

In this context, it is particularly preferable for compounds of group d)if compounds of the formula II are in the form of the diastereomers withthe relative configuration IIa

-   -   in particular are used in mixtures with a higher content of this        diastereomer compared with the other diastereomer or as the        isolated diastereomer,    -   and/or    -   the compounds of the formula II are used in the form of the        (+)-enantiomer, in particular in mixtures with a higher content        of the (+)-enantiomer compared with the (−)-enantiomer of a        racemic compound or as the isolated (+)-enantiomer.

In this context, it is particularly preferable if compound A chosen fromthe following group is used:

-   -   (1RS, 3RS,        6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,    -   (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,    -   (1RS, 3RS,        6RS)-6-dimethylaminomethyl-1-(3-hydroxy-phenyl)-cyclohexane-1,3-diol,    -   (1RS, 3SR,        6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,    -   (+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl)-phenol        or    -   (1RS,2RS,        5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl)-phenol,    -   preferably as the hydrochloride.

In a preferred embodiment, for the use according to the invention thecompound A in group e) is chosen from compounds according to formula IIIfor which:

-   -   X is chosen from        -   OH, F, Cl, OC(O)CH₃ or H, preferably OH, F or H, in            particular F or H,    -   and/or    -   R⁹ to R¹³, where 3 or 4 of the radicals R⁹ to R¹³ must        correspond to H, independently of one another are chosen from        -   H, Cl, F, OH, CF₂H, CF₃ or C₁₋₄-alkyl, saturated and            unsubstituted, branched or unbranched; OR¹⁴ or SR¹⁴, where            R¹⁴ is chosen from C₁₋₃-alkyl, saturated and unsubstituted,            branched or unbranched;            -   preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃        -   or R¹² and R¹¹ form a 3,4-OCH═CH ring    -   in particular characterized in that        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H,                OR¹⁴ or SCH₃, in particular OH or OC₁₋₃-alkyl,                preferably OH or OCH₃,        -   or        -   if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH,            OCH₃, Cl or F, preferably Cl, one of R¹⁰ or R¹² also            corresponds to H while the other corresponds to OH, OCH₃, Cl            or F, preferably Cl,        -   or        -   if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is chosen from            CF₃, CF₂H, Cl or F, preferably F,        -   or        -   if R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also            corresponds to H while the other is chosen from OH, OC₂H₅ or            OC₃H₇,        -   very particularly preferably        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, SH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH or                OR¹⁴, in particular OH or OC₁₋₃-alkyl, preferably OH or                OCH₃.

In this context, it is particularly preferable for compounds of group e)if compounds of the formula III are in the form of their diastereomerswith the relative configuration IIIa

-   -   in particular are used in mixtures with a higher content of this        diastereomer compared with the other diastereomer or as the        isolated diastereomer    -   and/or    -   the compounds of the formula III are used in the form of the        (+)-enantiomer, in particular in mixtures with a higher content        of the (+)-enantiomer compared with the (−)-enantiomer of a        racemic compound or as the isolated (+)-enantiomer.

In this context, it is particularly preferable if compound A chosen fromthe following group is used:

-   -   (+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclohexyl)-phenol,    -   (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or    -   (1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or    -   (−)-(1R,2R)-3-(2-dimethylamino methyl-cyclohexyl)-phenol,    -   (1R,2R)-3-(2-dimethylaminomethyl-cyclo hexyl)-phenol,    -   (−)-(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,    -   (1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,    -   preferably as the hydrochloride.

For a particularly preferred use, compound B is chosen from:

-   -   darifenacin, duloxetine, oxybutinin or tolterodine,    -   preferably is chosen from    -   duloxetine, oxybutinin or tolterodine,    -   preferably is chosen from    -   oxybutinin or tolterodine.

Although the uses according to the invention show only a low degree ofside effects, it may also be of advantage, for example to avoid certainforms of dependency, also to use morphine antagonists, in particularnaloxone, naltrexone and/or levallorphan, in addition to the combinationof compounds A and B.

The invention also provides an active compound combination of at leastone of the compounds A and at least one of the compounds B, withcompound A chosen from:

-   -   Group a) comprising:    -   tramadol, O-demethyltramadol or        O-demethyl-N-mono-demethyl-tramadol, optionally in the form of        their racemates, their isolated stereoisomers, in particular        enantiomers or diastereomers, or in the form of mixtures of the        stereoisomers, in particular the enantiomers or diastereomers,        in any desired mixing ratio; in the form of their acids or their        bases or in the form of their salts, in particular the        physiologically acceptable salts, or in the form of their        solvates, in particular the hydrates;    -   Group b) comprising:        -   codeine        -   dextropropxyphene        -   dihydrocodeine        -   diphenoxylate        -   ethylmorphine        -   meptazinol        -   nalbuphine        -   pethidine (meperidine)        -   tilidine        -   tramadol        -   viminol        -   butorphanol        -   dextromoramide        -   dezocine        -   diacetylmorphine (heroin)        -   hydrocodone        -   hydromorphone        -   ketobemidone        -   levomethadone        -   levomethadyl-acetate (1-α-acetylmethadol (LAAM))        -   levorphanol        -   morphine        -   nalorphine        -   oxycodone        -   pentazocine        -   piritramide        -   alfentanil        -   buprenorphine        -   etorphine        -   fentanyl        -   remifentanil        -   sufentanil    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form of their acids or their bases or in the form of their        salts, in particular the physiologically acceptable salts, or in        the form of their solvates, in particular the hydrates;    -   Group c) comprising:    -   1-phenyl-3-dimethylamino-propane compounds according to the        general formula I

-   -   wherein    -   X is chosen from OH, F, Cl, H or OC(O)R⁷, where R⁷ is chosen        from C₁₋₃-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted,    -   R¹ is chosen from C₁₋₄-alkyl, branched or unbranched, saturated        or unsaturated, unsubstituted or mono- or polysubstituted,    -   R² and R³ in each case independently of one another are chosen        from H or C₁₋₄-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted,    -   or    -   R² and R³ together form a saturated C₄₋₇-cycloalkyl radical,        unsubstituted or mono- or polysubstituted,        -   R⁹ to R¹³ in each case independently of one another are            chosen from H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴,            OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN,            COOR¹⁴, NO₂, CONR¹⁷R¹⁸; C₁₋₆-alkyl, branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted; phenyl, unsubstituted or mono- or            polysubstituted;        -   where R¹⁴ is chosen from C₁₋₆-alkyl; pyridyl, thienyl,            thiazolyl, phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted;            PO(O—C₁₋₄-alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl),            CO(C₁₋₅-alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ is            ortho-OCOC₁₋₃-alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is            C₁₋₄-alkyl or 4-morpholino, wherein in the radicals R¹⁴, R¹⁵            and R¹⁶ the alkyl groups can be branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted;        -   where R¹⁷ and R¹⁸ in each case independently of one another            are chosen from H; C₁₋₆-alkyl, branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted; phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted,    -   or    -   R⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O,        OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH₂)₄ or OCH═CHO ring,    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form shown or in the form of their acids or their bases or        in the form of their salts, in particular the physiologically        acceptable salts, or in the form of their solvates, in        particular the hydrates;    -   Group d) comprising:    -   substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds        according to the general formula II

-   -   wherein    -   X is chosen from OH, F, Cl, H or OC(O)R⁷, where R⁷ is chosen        from C₁₋₃-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted,    -   R¹ is chosen from C₁₋₄-alkyl, benzyl, CF₃, OH, OCH₂—C₆H₅,        O—C₁₋₄-alkyl, Cl or F and        -   R⁹ to R¹³ in each case independently of one another are            chosen from H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴,            OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN,            COOR¹⁴, NO₂, CONR¹⁷R¹⁸; C₁₋₆-alkyl, branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted; phenyl, unsubstituted or mono- or            polysubstituted;        -   where R¹⁴ is chosen from C₁₋₆-alkyl; pyridyl, thienyl,            thiazolyl, phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted;            PO(O—C₁₋₄-alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl),            CO(C₁₋₅-alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ is            ortho-OCOC₁₋₃-alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is            C₁₋₄-alkyl or 4-morpholino, wherein in the radicals R¹⁴, R¹⁵            and R¹⁶ the alkyl groups can be branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted;        -   where R¹⁷ and R18 in each case independently of one another            are chosen from H; C₁₋₆-alkyl, branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted; phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted,    -   or    -   R⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O,        OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH₂)₄ or OCH═CHO ring,    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form shown or in the form of their acids or their bases or        in the form of their salts, in particular the physiologically        acceptable salts, or in the form of their solvates, in        particular the hydrates;    -   and/or    -   Group e) comprising:    -   6-dimethylaminomethyl-1-phenyl-cyclohexane compounds according        to the general formula III

-   -   wherein    -   X is chosen from OH, F, Cl, H or OC(O)R⁷, where R⁷ is chosen        from C₁₋₃-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted, and    -   R⁹ to R¹³ in each case independently of one another are chosen        from H, F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴,        NR¹⁷R¹⁸, SOCH₃, SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂,        CONR¹⁷R¹⁸; C₁₋₆-alkyl, branched or unbranched, saturated or        unsaturated, unsubstituted or mono- or polysubstituted; phenyl,        unsubstituted or mono- or polysubstituted;        -   where R¹⁴ is chosen from C₁₋₆-alkyl; pyridyl, thienyl,            thiazolyl, phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted;            PO(O—C₁₋₄-alkyl)₂, CO(OC₁₋₅-alkyl), CONH—C₆H₄—(C₁₋₃-alkyl),            CO(C₁₋₅-alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ is            ortho-OCOC₁₋₃-alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is            C₁₋₄-alkyl or 4-morpholino, wherein in the radicals R¹⁴, R¹⁵            and R¹⁶ the alkyl groups can be branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted;        -   where R¹⁷ and R¹⁸ in each case independently of one another            are chosen from H; C₁₋₆-alkyl, branched or unbranched,            saturated or unsaturated, unsubstituted or mono- or            polysubstituted; phenyl, benzyl or phenethyl, in each case            unsubstituted or mono- or polysubstituted,    -   or    -   R⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O,        OCH═CH, CH═CHO, CH═C(CH3)O, OC(CH3)═CH, (CH₂)₄ or OCH═CHO ring,    -   with the proviso that if R⁹, R¹¹ and R¹³ correspond to H and one        of R¹⁰ or R¹² corresponds to H and the other corresponds to        OCH₃, X may not be OH,    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form shown or in the form of their acids or their bases or        in the form of their salts, in particular the physiologically        acceptable salts, or in the form of their solvates, in        particular the hydrates;    -   and with at least one of the compounds B chosen from:        -   the anti-muscarine agents: atropine, oxybutinin,            propiverine, propantheline, emepronium, trospium,            tolterodine, darifenacin and α,α-diphenylacetic acid            4-(N-methylpiperidyl) ester, as well as duloxetine,            imipramine and desmopressin,    -   optionally in the form of their racemates, their isolated        stereoisomers, in particular enantiomers or diastereomers, or in        the form of mixtures of the stereoisomers, in particular the        enantiomers or diastereomers, in any desired mixing ratio; in        the form of their acids or their bases or in the form of their        salts, in particular the physiologically acceptable salts, or in        the form of their solvates, in particular the hydrates.

For the active compound combination, it is particularly preferable ifthe compound A in group a) is chosen from:

-   -   tramadol, (+)-tramadol, (+)—O-demethyltramadol or        (+)—O-demethyl-N-mono-demethyl-tramadol,    -   preferably tramadol or (+)-tramadol,    -   in particular (+)-tramadol.

For the active compound combination, it is particularly preferable ifthe compound A in group b) is chosen from:

-   -   codeine    -   dextropropxyphene    -   dihydrocodeine    -   diphenoxylate    -   ethylmorphine    -   meptazinol    -   nalbuphine    -   pethidine (meperidine)    -   tilidine    -   viminol    -   butorphanol    -   dezocine    -   nalorphine    -   pentazocine    -   buprenorphine        preferably    -   codeine    -   dextropropxyphene    -   dihydrocodeine    -   meptazinol    -   nalbuphine    -   tilidine    -   buprenorphine

For the active compound combination, it is particularly preferable ifthe compound A in group c) is chosen from compounds according to formulaI for which:

-   -   X is chosen from        -   OH, F, Cl, OC(O)CH₃ or H, preferably OH, F, OC(O)CH₃ or H,    -   and/or    -   R¹ is chosen from        -   C₁₋₄-alkyl, saturated and unsubstituted, branched or            unbranched; preferably CH₃, C₂H₅, C₄H₉ or t-butyl, in            particular CH₃ or C₂H₅,    -   and/or    -   R² and R³ independently of one another are chosen from        -   H, C₁₋₄-alkyl, saturated and unsubstituted, branched or            unbranched; preferably H, CH₃, C₂H₅, i-propyl or t-butyl, in            particular H or CH₃, preferably R³═H,        -   or        -   R² and R³ together form a C₅₋₆-cycloalkyl radical, saturated            or unsaturated, unsubstituted or mono- or polysubstituted,            preferably saturated and unsubstituted, in particular            cyclohexyl.    -   and/or    -   R⁹ to R¹³, where 3 or 4 of the radicals R⁹ to R¹³ must        correspond to H, independently of one another are chosen from        -   H, Cl, F, OH, CF₂H, CF₃ or C₁₋₄-alkyl, saturated and            unsubstituted, branched or unbranched; OR¹⁴ or SR¹⁴, where            R¹⁴ is chosen from C₁₋₃-alkyl, saturated and unsubstituted,            branched or unbranched;            -   preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃        -   or R¹² and R¹¹ form a 3,4-OCH═CH ring    -   in particular        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H,                OCH₃ or SCH₃        -   or        -   if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH,            OCH₃, Cl or F, preferably Cl, one of R¹⁰ or R¹² also            corresponds to H while the other corresponds to OH, OCH₃, Cl            or F, preferably Cl,        -   or        -   if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is chosen from            CF₃, CF₂H, Cl or F, preferably F,        -   or        -   if R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also            corresponds to H while the other is chosen from OH, OC₂H₅ or            OC₃H₇.

In this context, it is particularly preferable for compounds of group c)if the compounds of the formula I where R³═H are in the form of thediastereomers with the relative configuration 1a

-   -   in particular in mixtures with a higher content of this        diastereomer compared with the other diastereomer or as the        isolated diastereomer and/or    -   the compounds of the formula I are in the form of the        (+)-enantiomer, in particular in mixtures with a higher content        of the (+)-enantiomer compared with the (−)-enantiomer of a        racemic compound or as the isolated (+)-enantiomer.

In this context, it is particularly preferable if compound A is chosenfrom the following group:

-   -   (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol    -   (2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,    -   (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,    -   (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol,    -   (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethylamino-2-methyl-pentan-3-ol,    -   (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanyl-phenyl)-pentan-3-ol,    -   (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethyl-pentan-3-ol,    -   (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenol,    -   (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,    -   (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,    -   (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,    -   (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,    -   (+)-(1R,2R)-acetic acid        3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl-propyl        ester,    -   (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxy-phenyl)-propan-1-ol,    -   (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol,    -   (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenol,    -   (2RS,3RS)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol        and    -   (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol,    -   preferably as the hydrochloride.

For the active compound combination, it is particularly preferable ifthe compound A in group d) is chosen from compounds according to formulaII for which:

-   -   X is chosen from        -   OH, F, Cl, OC(O)CH₃ or H, preferably OH, F or H, in            particular OH,    -   and/or    -   R¹ is chosen from        -   C₁₋₄-alkyl, CF₃, OH, O—C₁₋₄-alkyl, Cl or F, preferably OH,            CF₃ or CH₃,    -   and/or    -   R⁹ to R¹³, where 3 or 4 of the radicals R⁹ to R¹³ must        correspond to H, independently of one another are chosen from        -   H, Cl, F, OH, CF₂H, CF₃ or C₁₋₄-alkyl, saturated and            unsubstituted, branched or unbranched; OR¹⁴ or SR¹⁴, where            R¹⁴ is chosen from C₁₋₃-alkyl, saturated and unsubstituted,            branched or unbranched;            -   preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃        -   or R¹² and R¹¹ form a 3,4-OCH═CH ring    -   in particular        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H,                OR¹⁴ or SCH₃, in particular OH or OC₁₋₃-alkyl,                preferably OH or OCH₃,        -   or        -   if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH,            OCH₃, Cl or F, preferably Cl, one of R¹⁰ or R¹² also            corresponds to H while the other corresponds to OH, OCH₃, Cl            or F, preferably Cl,        -   or        -   if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is chosen from            CF₃, CF₂H, Cl or F, preferably F,        -   or        -   if R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also            corresponds to H while the other is chosen from OH, OC₂H₅ or            OC₃H₇.        -   very particularly preferably        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:        -   Cl, F, OH, SH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH or            OR¹⁴, in particular OH or OC₁₋₃-alkyl, preferably OH or            OCH₃.

In this context, it is particularly preferable for compounds of group d)if the compounds of the formula II are in the form of the diastereomerswith the relative configuration IIa

-   -   in particular in mixtures with a higher content of this        diastereomer compared with the other diastereomer or as the        isolated diastereomer, and/or    -   the compounds of the formula II are in the form of the        (+)-enantiomer, in particular in mixtures with a higher content        of the (+)-enantiomer compared with the (−)-enantiomer of a        racemic compound or as the isolated (+)-enantiomer.

In this context, it is particularly preferable if compound A is chosenfrom the following group:

-   -   (1RS, 3RS,        6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane—1,3-diol,    -   (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,    -   (1RS,        3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxy-phenyl)-cyclohexane-1,3-diol,    -   (1RS, 3SR,        6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,    -   (+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl)-phenol        or    -   (1RS, 2RS,        5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl)-phenol,    -   preferably as the hydrochloride.

For the active compound combination, it is particularly preferable ifthe compound A in group e) is chosen from compounds according to formulaIII for which:

-   -   X is chosen from        -   OH, F, Cl, OC(O)CH₃ or H, preferably OH, F or H, in            particular F or H,    -   and/or    -   R⁹ to R¹³, where 3 or 4 of the radicals R⁹ to R¹³ must        correspond to H, independently of one another are chosen from        -   H, Cl, F, OH, CF₂H, CF₃ or C₁₋₄-alkyl, saturated and            unsubstituted, branched or unbranched; OR¹⁴ or SR¹⁴, where            R¹⁴ is chosen from C₁₋₃-alkyl, saturated and unsubstituted,            branched or unbranched;            -   preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃        -   or R¹² and R¹¹ form a 3,4-OCH═CH ring    -   in particular characterized in that        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H,                OR¹⁴ or SCH₃, in particular OH or OC₁₋₃-alkyl,                preferably OH or OCH₃,        -   or        -   if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH,            OCH₃, Cl or F, preferably Cl, one of R¹⁰ or R¹² also            corresponds to H while the other corresponds to OH, OCH₃, Cl            or F, preferably Cl,        -   or        -   if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is chosen from            CF₃, CF₂H, Cl or F, preferably F,        -   or        -   if R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also            corresponds to H while the other is chosen from OH, OC₂H₅ or            OC₃H₇,        -   very particularly preferably        -   if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also            corresponds to H while the other is chosen from:            -   Cl, F, OH, SH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH or                OR¹⁴, in particular OH or OC₁₋₃-alkyl, preferably OH or                OCH₃.

In this context, it is particularly preferable for compounds of group e)if the compounds of the formula III are in the form of theirdiastereomers with the relative configuration IIIa

-   -   in particular in mixtures with a higher content of this        diastereomer compared with the other diastereomer or as the        isolated diastereomer and/or    -   the compounds of the formula III are in the form of the        (+)-enantiomer, in particular in mixtures with a higher content        of the (+)-enantiomer compared with the (−)-enantiomer of a        racemic compound or as the isolated (+)-enantiomer.

In this context, it is particularly preferable if compound A is chosenfrom the following group:

-   -   (+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclohexyl)-phenol,    -   (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or    -   (1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or    -   (−)-(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol,    -   (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol,    -   (−)-(1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,    -   (1R,2R)-[2-(3-methoxy-phenyl)-cyclohexylmethyl]-dimethylamine,    -   preferably as the hydrochloride.

In a generally particularly preferred form of the active compoundcombination according to the invention the compound B is chosen from:

-   -   darifenacin, duloxetine, oxybutinin or tolterodine,    -   preferably is chosen from    -   duloxetine, oxybutinin or tolterodine,    -   preferably is chosen from    -   oxybutinin or tolterodine.

The invention also provides a medicament, preferably for treatment of anincreased urge to urinate or urinary incontinence, comprising an activecompound combination according to the invention and optionally suitableadditives and/or auxiliary substances.

Suitable additives and/or auxiliary substances in the context of thisinvention are all the substances known to the expert from the prior artfor achieving pharmaceutical formulations. The choice of these auxiliarysubstances and the amounts thereof to be employed depend on whether themedicament is to be administered orally, intravenously,intraperitoneally, intradermally, intramuscularly, intranasally,buccally or locally. Formulations in the form of tablets, chewabletablets, coated tablets, capsules, granules, drops, juices or syrups aresuitable for oral administration, and solutions, suspensions, easilyreconstitutable dry formulations and sprays are suitable for parenteral,topical and inhalatory administration. Suppositories for use in therectum are a further possibility. The use in a depot in dissolved form,a carrier film or a patch, optionally with the addition of agents whichpromote penetration of the skin, are examples of suitable forms forpercutaneous administration. Examples of auxiliary substances andadditives for the oral administration forms are disintegrating agents,lubricants, binders, fillers, mold release agents, with appropriatesolvents, flavorings, sugar, in particular carrier agents, diluents,dyestuffs, antioxidants, etc. Waxes and fatty acid esters, inter alia,can be used for suppositories and carrier substances, preservatives,suspension auxiliaries etc. can be used for compositions for parenteraladministration. The amounts of active compound to be administered topatients vary as a function of the weight of the patient, the mode ofadministration and the severity of the disease. The compounds accordingto the invention can be released in a delayed manner from formulationforms for oral, rectal or percutaneous use. In the indication accordingto the invention, appropriate sustained release formulations, inparticular in the form of a “once-daily” preparation which has to betaken only once a day, are particularly preferred.

Medicaments which comprise at least 0.05 to 90.0% of the activecompound, in particular dosages with a low action, in order to avoidside effects or analgesic actions, are furthermore preferred. 0.1 to5,000 mg/kg, in particular 1 to 500 mg/kg, preferably 2 to 250 mg/kg ofbody weight of at least one compound of the formula I are conventionallyadministered. However, administration of 0.01-5 mg/kg, preferably 0.03to 2 mg/kg, in particular 0.05 to 1 mg/kg of body weight, is alsolikewise preferred and conventional.

Auxiliary substances can be, for example: water, ethanol, 2-propanol,glycerol, ethylene glycol, propylene glycol, polyethylene glycol,polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose,molasses, starch, modified starch, gelatins, sorbitol, inositol,mannitol, microcrystalline cellulose, methylcellulose,carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol,polyvinylpyrrolidone, paraffins, waxes, naturally occurring andsynthetic rubbers, gum acacia, alginates, dextran, saturated andunsaturated fatty acids, stearic acid, magnesium stearate, zincstearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesameoil, coconut oil, groundnut oil, soya bean oil, lecithin, sodiumlactate, polyoxyethylene and -propylene fatty acid esters, sorbitanfatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbicacid, tannic acid, sodium chloride, potassium chloride, magnesiumchloride, calcium chloride, magnesium oxide, zinc oxide, silicondioxide, titanium oxide, titanium dioxide, magnesium sulfate, zincsulfate, calcium sulfate, potash, calcium phosphate, dicalciumphosphate, potassium bromide, potassium iodide, talc, kaolin, pectin,crospovidone, agar and bentonite.

The medicaments and pharmaceutical compositions according to theinvention are prepared with the aid of agents, devices, methods andprocesses which are well-known in the prior art of pharmaceuticalformulation, such as are described, for example, in “Remington'sPharmaceutical Sciences”, ed. A. R. Gennaro, 17th ed., Mack PublishingCompany, Easton, Pa. (1985), in particular in part 8, chapter 76 to 93.

Thus, e.g., for a solid formulation, such as a tablet, the activecompound of the medicament can be granulated with a pharmaceuticalcarrier, e.g., conventional tablet constituents, such as maize starch,lactose, sucrose, sorbitol, talc, magnesium stearate, dicalciumphosphate or pharmaceutically acceptable gums, and pharmaceuticaldiluents, such as, e.g., water, in order to form a solid compositionwhich comprises the active compound in homogeneous distribution.Homogeneous distribution is understood here as meaning that the activecompound is distributed uniformly over the entire composition, so thatthis can be easily divided into unit dose forms, such as tablets, pillsor capsules, with the same action. The solid composition is then dividedinto unit dose forms. The tablets or pills of the medicament accordingto the invention or of the compositions according to the invention canalso be coated, or compounded in another manner, in order to provide adose form with delayed release. Suitable coating compositions are, interalia, polymeric acids and mixtures of polymeric acids with materialssuch as, e.g., shellac, cetyl alcohol and/or cellulose acetate.

Although the medicaments according to the invention show only a lowdegree of side effects, it may be of advantage, for example to avoidcertain forms of dependency, also to use morphine antagonists, inparticular naloxone, naltrexone and/or levallorphan, in addition to thecombination of compounds A and B.

The invention also relates to a method for treatment of an increasedurge to urinate or urinary incontinence, in which the active compoundcombination of compound A and compound B, in particular in atherapeutically active (in each case) dosage, is used.

The following examples are intended to explain the invention without thesubject matter of the invention being limited thereto.

EXAMPLES Example 1 Test System of Cystometry on Anaesthetized Naïve Rats

The cystometric investigation on naive female rats was carried out bythe method of Kimura et al. (Kimura et al., 1996, Int. J. Urol.3:218-227). The abdomen of anaesthetized, ventilated rats is opened upand the ureter is ligated. The urine is drained from the kidneys. Acatheter is inserted into the bladder and fixed. Saline is infused intothe bladder via this by means of an infusion pump, until the bladdershows rhythmic spontaneous activity in the form of contractions whichcan be recorded via a connected pressure transducer. After stablestarting values are reached, the test substance is administeredintravenously. An influence on bladder function manifests itself viasuppression of the spontaneous contractions.

In the present example, compound A((+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol;hydrochloride) in the dosage of 0.1 mg/kg intravenous was combined withcompound B (oxybutynin) in the dosage of 0.03 mg/kg intravenous and theaction of this combination was compared with that of the individualsubstances. The individual substances and combination showed aninhibition of the rate of contractions (micturition events/min). Thedata are summarized in the following table.

Compound A Compound A Compound B 0.1 mg/kg i.v. + Vehicle 0.1 mg/kg 0.03mg/kg compound B control Substance i.v. i.v 0.3 mg/kg i.v. i.v.Inhibition of 21.7% 10.7% 42.5% 4.0% the rate of contractions comparedwith the pretest [% MPE]

A suppression of spontaneous contractions in the rats was measurablewith all the substances and combinations listed here.

The combination of substances which was investigated shows a positiveaction on bladder regulation and is thus suitable for treatment ofurinary incontinence.

Example 2 Parenteral Administration Form

20 g tramadol and 1 g tolterodine is dissolved in 1 l of water forinjection purposes at room temperature and the solution is then adjustedto isotonic conditions by addition of NaCl.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

The invention claimed is:
 1. A composition of matter comprising as anadmixture(+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol ora salt thereof with a physiologically tolerated acid and oxybutynin or asalt thereof with a physiologically tolerated acid at dosages thatprovide a synergistic effect for the treatment of urinary incontinence.2. The composition of matter of claim 1, wherein one or more of(+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-oland oxybutynin is present in the form of a free base.
 3. The compositionof matter of claim 1, wherein oxybutynin is present in the form of anisolated enantiomer.
 4. The composition of matter of claim 1, whereinoxybutynin is present in the form of a mixture of stereoisomers.
 5. Thecomposition of matter of claim 4, wherein oxybutynin is present in theform of a racemic mixture.
 6. The composition of matter of claim 1,wherein(+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol isin the form of a hydrochloride salt.
 7. A pharmaceutical formulationcomprising as an active compound combination a composition of matteraccording to claim 1 and at least one pharmaceutically suitable additiveor auxiliary substance.